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Aflibercept, Ziv-Aflibercept, and Conbercept

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Aflibercept, Ziv-Aflibercept, and Conbercept View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector de Oliveira Dias et al. Int J Retin Vitr (2016) 2:3 DOI 10.1186/s40942-016-0026-y International Journal of Retina and Vitreous REVIEW Open Access Fusion proteins for treatment of retinal diseases: aflibercept, ziv‑aflibercept, and conbercept João Rafael de Oliveira Dias* , Gabriel Costa de Andrade, Eduardo Amorim Novais, Michel Eid Farah and Eduardo Büchele Rodrigues Abstract In the last few years, monoclonal antibodies have revolutionized the treatment of retinal neovascular diseases. More recently, a different class of drugs, fusion proteins, has provided an alternative treatment strategy with pharmacologi- cal differences. In addition to commercially available aflibercept, two other drugs, ziv-aflibercept and conbercept, have been studied in antiangiogenic treatment of ocular diseases. In this scenario, a critical review of the currently available data regarding fusion proteins in ophthalmic diseases may be a timely and important contribution. Afliber- cept, previously known as VEGF Trap Eye, is a fusion protein of VEGF receptors 1 and 2 and a treatment for several retinal diseases related to angiogenesis. It has firmly joined ranibizumab and bevacizumab as an important thera- peutic option in the management of neovascular AMD-, DME- and RVO-associated macular edema. Ziv-aflibercept, a systemic chemotherapeutic agent approved for the treatment of metastatic colorectal cancer, has recently drawn attention because of its potential for intravitreal administration, since it was not associated with ERG-related signs of toxicity in an experimental study and in human case reports. Conbercept is a soluble receptor decoy that blocks all isoforms of VEGF-A, VEGF-B, VEGF-C, and PlGF, which has a high binding affinity for VEGF and a long half-life in vitre- ous. It has been studied in a phase three clinical trial and has shown efficacy and safety. This review discusses three fusion proteins that have been studied in ophthalmology, aflibercept, ziv-aflibercept and conbercept, with emphasis on their clinical application for the treatment of retinal diseases. Keywords: Fusion proteins, Aflibercept, Ziv-aflibercept, Conbercept, Vascular endothelial growth factor (VEGF), VEGF Trap Eye Introduction angiogenesis [2]. Three VEGF receptor (VEGFR) sub- Vascular endothelial growth factor (VEGF) is a 36- to types have been identified: VEGFR 1–3, among which 46-kDa homodimeric glycoprotein that acts as an angio- VEGFR-1 binds VEGF with the highest affinity, while genic cytokine, inducing mitosis [1]. It has six members, VEGFR-2 is the most important in angiogenesis [2]. VEGF-A to -E, and placental growth factor (PlGF), of Many cell types in the retina produce VEGF. These which VEGF-A is the most important cytokine involved include the retinal pigment epithelium (RPE), vascular in angiogenesis. There are several isoforms of VEGF- endothelial cells, pericytes, retinal neurons, Müller cells A in humans: VEGF121, VEGF145, VEGF165, VEGF183, and astrocytes [3, 4]. VEGF is secreted by the RPE and VEGF189 and VEGF206. Of these, VEGF165 is the most retinal cells in response to hypoxia secondary to ischemic common VEGF-A isoform and the most important for retinal disorders. Upregulation of VEGF results in angio- genesis, increased vascular permeability, and the produc- tion of pro-inflammatory cytokines [5]. *Correspondence: [email protected] Over the past decade, the use of intravitreal pharma- Department of Ophthalmology, Federal University of São Paulo-Paulista Medical School, Rua Botucatu, 821, 1st Floor, São Paulo, SP 04023‑062, cotherapy to block VEGF has become common and has Brazil significantly improved visual outcomes in patients with © 2016 de Oliveira Dias et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons. org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. de Oliveira Dias et al. Int J Retin Vitr (2016) 2:3 Page 2 of 9 neovascular age-related macular degeneration (AMD), approximately 15 % glycosylation to give a total molecu- diabetic macular edema (DME) and retinal vein occlu- lar weight of 115 kDa. As a designed molecule featuring sion (RVO)-associated macular edema (ME) [6–8]. These optimal pharmacologic characteristics to inhibit intraoc- retinal diseases are characterized by the production of ular VEGF, intravitreal aflibercept injection (IAI) offers increased levels of intraocular VEGF and development of improved binding affinity and superior pharmacoki- ME resulting in dysfunction of central and sharp vision. netics in an iso-osmotic formulation. Aflibercept may VEGF also mediates the development of neovasculariza- have approximately 100-fold greater binding affinity for tion in these conditions and may lead to severe irreversi- VEGF-A than does either bevacizumab or ranibizumab ble vision loss. The administration of an anti-VEGF agent [9, 10]. It binds to all VEGF-A isoforms and the related in the vitreous cavity of patients with these disorders VEGFR-1 ligands, VEGF-B and PlGF, and it is the only lowers intraocular VEGF, reduces vascular permeabil- United States Food and Drug Administration (FDA)- ity and is associated with arrested growth of and leakage approved VEGF Trap for intravitreal use [9, 14]. from neovessels in choroidal neovascularization (CNV) Ziv-aflibercept (Zaltrap; co-developed by Sanofi- [6, 9]. Aventis and Regeneron Pharmaceuticals, Inc, Tarrytown, VEGF blockers used to treat eye diseases have included NY, USA), is identical to aflibercept, except for its excipi- an aptamer, a humanized monoclonal antibody, an anti- ents and higher osmolarity. While aflibercept is available body fragment, and, more recently, cytokine traps [6, 10– in a single-use glass vial designed to provide 0.05 ml of 12]. The purpose of this review is to provide an overview 40 mg/ml solution (2 mg) for intravitreal injection, ziv- of three fusion proteins that have been studied for the aflibercept is available as 100 mg per 4 ml (25 mg per ml) treatment of retinal diseases: aflibercept, ziv-aflibercept solution or 200 mg per 8 ml (25 mg per ml) solution, in and conbercept. a single-use vial. Aflibercept is iso-osmolar, whereas ziv- aflibercept is hyperosmolar (1000 mOsm/l) relative to the Fusion proteins: history, chemistry, production, vitreous [15, 16]. and biology In 2012, ziv-aflibercept received United States FDA In 2002, Holash et al. published the first paper reporting approval for use in combination with FOLFIRI (folinic the development and in vivo study of VEGF Trap for can- acid, fluorouracil and irinotecan) in patients with cer treatment. VEGF Trap was created by fusing the first metastatic colorectal cancer that is resistant to or has three immunoglobulin (Ig) domains of VEGFR-1 to the progressed after oxaliplatin-based regimens such as FOL- Fc region of human IgG1. Three additional VEGF traps FOX (folinic acid, fluorouracil, oxaliplatin) [16]. Its intra- were then engineered on the basis of that initial molecule: vitreal off-label use in humans was not associated with the VEGF Trap B1 (in which a highly basic 10-amino acid toxicity, inflammation or higher rate of cataract induction sequence was removed from the third Ig domain of the [11, 17, 18]. Although this drug has a higher osmolarity parental trap), the VEGF Trap B2 (in which the entire when compared to aflibercept, serum and intraocular first Ig domain from VEGF Trap B1 was removed), and osmolarity may not be significantly altered after intravit- VEGF Trap R1R2 (the result of the fusion of the second real injection of ziv-aflibercept [19]. Ig domain of VEGFR-1 with the third domain of VEGFR- In 2008, Zhang et al. published the first study of con- 2). These modifications enhanced R1R2 trap affinity bercept (KH902) (Lumitin; Chengdu Kanghong Bio- for VEGF-A. The initial parental VEGF Trap had very tech, Ltd., Sichuan, People’s Republic of China) in an high affinity for VEGF-A and PlGF, but was a strongly experimental CNV monkey model [20]. Conbercept is positively charged molecule that bound to the extracel- a full human DNA sequence with a molecular weight of lular matrix in addition to VEGF-A and PlGF. Modifica- 143 kDa produced with Chinese hamster ovary cells, and tions resulted in a less positively charged molecule that it combines ligand-binding elements taken from extracel- retained high affinity for VEGF-A and VEGF-B as well lular domain 2 of VEGF receptors 1 (Flt-1) and extracel- as PlGF, but did not specifically bind to the extracellular lular domain 3 and 4 of VEGF receptors 2 (KDR) fused to matrix [13]. the Fc portion of human IgG1 [20–22]. This drug binds The current aflibercept, previously called VEGF Trap VEGF dimers in a 1:1 ratio with a “two-fisted grasp” Eye, evolved from the parental VEGF Trap studied by that resembles the action of aflibercept. The difference Holash et al. This fully human protein consists of an between conbercept and aflibercept is that the former all human amino acid sequence, which minimizes the also contains domain 4 of VEGFR-2, which was proved potential for immunogenicity in human patients [13]. in previous studies to be essential to the receptor [10, 23, Aflibercept (Eylea; Regeneron, Tarrytown, NY, USA, and 24]. Domain 4 does not participate in ligand binding but Bayer, Leverkusen, Germany) is a dimeric glycoprotein structure analysis of ligand-bound VEGFR has revealed with a protein molecular weight of 96.9 kDa. It contains that this domain might be involved in specific homotypic de Oliveira Dias et al.
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